Whole-exome sequencing reveals a rare missense variant in DTNA in an Iranian pedigree with early-onset atrial fibrillation

Malakootian, Mahshid; Jalilian, Masoumeh; Kalayinia, Samira; Moghadam, Maryam Hosseini; Heidarali, Mona; Haghjoo, Majid

doi:10.1186/s12872-022-02485-0

Cited by 6 publications

(3 citation statements)

References 39 publications

(38 reference statements)

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“…Furthermore, a missense variant (c.G681C, p.E227D, rs1477078144) in the dystrobrevin alpha (DTNA) gene associated with early-onset AF affects the Rho-(RAS homolog) signaling pathway. Variants in DTNA and the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene underscore the genetic complexity underlying AF [ 82 ].…”

Section: Genetic Factors and Insights Into Afmentioning

confidence: 99%

The Role of KACh Channels in Atrial Fibrillation

Mitrokhin,

Hadzi-Petrushev,

Kazanski

et al. 2024

Cells

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This manuscript explores the intricate role of acetylcholine-activated inward rectifier potassium (KACh) channels in the pathogenesis of atrial fibrillation (AF), a common cardiac arrhythmia. It delves into the molecular and cellular mechanisms that underpin AF, emphasizing the vital function of KACh channels in modulating the atrial action potential and facilitating arrhythmogenic conditions. This study underscores the dual nature of KACh activation and its genetic regulation, revealing that specific variations in potassium channel genes, such as Kir3.4 and K2P3.1, significantly influence the electrophysiological remodeling associated with AF. Furthermore, this manuscript identifies the crucial role of the KACh-mediated current, IKACh, in sustaining arrhythmia through facilitating shorter re-entry circuits and stabilizing the re-entrant circuits, particularly in response to vagal nerve stimulation. Experimental findings from animal models, which could not induce AF in the absence of muscarinic activation, highlight the dependency of AF induction on KACh channel activity. This is complemented by discussions on therapeutic interventions, where KACh channel blockers have shown promise in AF management. Additionally, this study discusses the broader implications of KACh channel behavior, including its ubiquitous presence across different cardiac regions and species, contributing to a comprehensive understanding of AF dynamics. The implications of these findings are profound, suggesting that targeting KACh channels might offer new therapeutic avenues for AF treatment, particularly in cases resistant to conventional approaches. By integrating genetic, cellular, and pharmacological perspectives, this manuscript offers a holistic view of the potential mechanisms and therapeutic targets in AF, making a significant contribution to the field of cardiac arrhythmia research.

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Section: Genetic Factors and Insights Into Afmentioning

confidence: 99%

The Role of KACh Channels in Atrial Fibrillation

Mitrokhin,

Hadzi-Petrushev,

Kazanski

et al. 2024

Cells

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“…However, aggregating investigations have convincingly substantiated that genetic determinants exert critical roles in the initiation and perpetuation of AF, especially for idiopathic/familial AF, and, to date, a great number of rare AF-causing variations in >60 genes have been causally related to AF, amidst which the overwhelming majority encode ion channel subunits, myocardial structural proteins, signaling molecules, cardiac transcription factors, and connexins [ 52 , 53 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. In addition, pan-genomic association research has revealed that common variants at ~140 genetic loci are implicated with enhanced vulnerability to AF, though merely a small fraction of these recognized variants have been experimentally validated to be pathogenic for AF thus far [ 52 ].…”

Section: Introductionmentioning

confidence: 99%

Discovery of TBX20 as a Novel Gene Underlying Atrial Fibrillation

Li,

Guo

et al. 2023

Biology

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Atrial fibrillation (AF), the most prevalent type of sustained cardiac dysrhythmia globally, confers strikingly enhanced risks for cognitive dysfunction, stroke, chronic cardiac failure, and sudden cardiovascular demise. Aggregating studies underscore the crucial roles of inherited determinants in the occurrence and perpetuation of AF. However, due to conspicuous genetic heterogeneity, the inherited defects accounting for AF remain largely indefinite. Here, via whole-genome genotyping with genetic markers and a linkage assay in a family suffering from AF, a new AF-causative locus was located at human chromosome 7p14.2-p14.3, a ~4.89 cM (~4.43-Mb) interval between the markers D7S526 and D7S2250. An exome-wide sequencing assay unveiled that, at the defined locus, the mutation in the TBX20 gene, NM_001077653.2: c.695A>G; p.(His232Arg), was solely co-segregated with AF in the family. Additionally, a Sanger sequencing assay of TBX20 in another family suffering from AF uncovered a novel mutation, NM_001077653.2: c.862G>C; p.(Asp288His). Neither of the two mutations were observed in 600 unrelated control individuals. Functional investigations demonstrated that the two mutations both significantly reduced the transactivation of the target gene KCNH2 (a well-established AF-causing gene) and the ability to bind the promoter of KCNH2, while they had no effect on the nuclear distribution of TBX20. Conclusively, these findings reveal a new AF-causative locus at human chromosome 7p14.2-p14.3 and strongly indicate TBX20 as a novel AF-predisposing gene, shedding light on the mechanism underlying AF and suggesting clinical significance for the allele-specific treatment of AF patients.

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“…Whole-exome sequencing (WES) is a viable and powerful technique that beyond traditional candidate gene and locus-mapping methods provides an efficient approach to find the genetic cause of heterogeneous diseases [ 16 , 17 ] like DCM [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Dilated cardiomyopathy caused by a pathogenic nucleotide variant in RBM20 in an Iranian family

et al. 2022

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Introduction Dilated cardiomyopathy (DCM) is characterized by the dilation and impaired contraction of 1 or both ventricles and can be caused by a variety of disorders. Up to 50% of idiopathic DCM cases have heritable familial diseases, and the clinical screening of family members is recommended. Identifying a genetic cause that can explain the DCM risk in the family can help with better screening planning and clinical decision-making. Whole-exome sequencing (WES) has aided significantly in the detection of causative genes in many genetically heterogeneous diseases. In the present study, we applied WES to identify the causative genetic variant in a family with heritable DCM. Methods WES was applied to identify genetic variants on a 26-year-old man as the proband of a family with DCM. Subsequently, Sanger sequencing was performed to confirm the variant in the patient and all the available affected and unaffected family members. The pathogenicity of the variant was evaluated through co-segregation analysis in the family and employment of in silico predictive software. Results WES demonstrated the missense pathogenic heterozygous nucleotide variant, c.1907G > A, (p.Arg636His, rs267607004, NM_0011343), in exon 9 of the RBM20 gene in the proband. The variant was co-segregated in all the affected family members in a heterozygous form and the unaffected family members. The in silico analysis confirmed the variant as pathogenic. Conclusion Pathogenic RBM20 nucleotide variants are associated with arrhythmogenic DCM. We believe that our report is the first to show an RBM20 variant in Iranian descent associated with DCM.

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Whole-exome sequencing reveals a rare missense variant in DTNA in an Iranian pedigree with early-onset atrial fibrillation

Cited by 6 publications

References 39 publications

The Role of KACh Channels in Atrial Fibrillation

The Role of KACh Channels in Atrial Fibrillation

Discovery of TBX20 as a Novel Gene Underlying Atrial Fibrillation

Dilated cardiomyopathy caused by a pathogenic nucleotide variant in RBM20 in an Iranian family

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